Study to overcome metastasis and targeted drug-resistance of lung cancer

• Project/Area Number: 24390209
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kanazawa University
• Principal Investigator: YANO Seiji 金沢大学, がん進展制御研究所, 教授 (30294672)
• Co-Investigator(Kenkyū-buntansha): EBI Hiromichi 金沢大学, がん進展制御研究所, 助教 (00645145) ; OHTSUBO Koshiro 金沢大学, 大学病院, 講師 (60361987)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2014: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: 分子標的薬耐性 / 脳転移 / 骨転移 / がん性胸膜炎 / 転移 / イメージング / がん性胸水 / がん性髄膜炎 / 肺がん / ALK阻害薬耐性 / BIM遺伝子多型 / EGFR阻害薬耐性 / mTOR阻害薬 / 個別化医療 / ボリノスタット

Outline of Final Research Achievements

To elucidate mechanism of targeted drug resistance in metastatic lesions, we established in vivo imaging models for pleural carcinomatosis and bone/brain metastases, which are resistant to targeted drugs, of EGFR mutant or ALK fusion positive lung cancer cell lines. We found that resistant tumors consist of a heterogeneous mixture of functionally distinct cancer cells with different resistant mechanisms. Moreover, our observation indicated that we should be careful for toxicity of combined therapy which overcome targeted drug resistance caused by multiple mechanisms.

Research Products

• [Journal Article] Ability of a convolutional neural network to differentiate between mouse and human cell lines and their radioresistant clones using microscopic images. (2019)
  • Author(s): Toratani, M., Konno, M., Asai. A., Koseki, J., Kawamoto, K., Tamari, K., Li, Z., Sakai, D., Kudo, T., Satoh, T., Sato, K., Motooka, D., Okuzaki, D., Doki, Y., Mori, M., Ogawa, K., Ishii, H.
  • Journal Title: Cancer Res Volume: 72(16) Pages: 1283-1295
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Near-Comprehensive Resequencing of Cancer-Associated Genes in Surgically Resected Metastatic Liver Tumors of Gastric Cancer. (2019)
  • Author(s): J. Asai, H. Takenaka, S. Hirakawa, J. Sakabe, A. Hagura, S. Kishimoto, K. Maruyama, K. Kajiya, S. Kinoshita, Y. Tokura, N. Katoh
  • Journal Title: American Journal of Pathology Volume: 181 Pages: 1180-1189
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment. (2018)
  • Author(s): Harada T, Yatabe Y, Takeshita M, Koga T, et al
  • Journal Title: Anticancer Res Volume: 17 Pages: 1114-1114
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor sidedness and enriched gene groups for efficacy of first-line cetuximab treatment in metastatic colorectal cancer. (2018)
  • Author(s): Sugiyama M., et al
  • Journal Title: Mol Cancer Ther. Volume: 10 Pages: 1136-1146
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations. (2015)
  • Author(s): Ebi H, Yano S, et al.
  • Journal Title: Journal of Thoracic Oncology Volume: 10 Pages: 59-66
  • DOI: 10.1097/jto.0000000000000371
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Therapeutic activity of glycoengineered anti-GM2 antibodies against malignant pleural mesothelioma. (2015)
  • Author(s): Li Q, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 106 Pages: 102-107
  • DOI: 10.1111/cas.12575
  • NAID: 120005666336
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line. (2015)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: Cancer Sci. Volume: 106 Pages: 244-252
  • DOI: 10.1111/cas.12600
  • NAID: 120005830611
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LPP inhibits collective cell migration during lung cancer dissemination. (2015)
  • Author(s): Tanaka M, Yano S, et al.
  • Journal Title: Oncogene Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Triple inhibition of EGFR, Met, and VEGF suppresses regrowth of HGF-triggered, erlotinib-resistant lung cancer harboring an EGFR mutation. (2014)
  • Author(s): Nakade J, Yano S, et al.
  • Journal Title: Journal of Thoracic Oncology Volume: 9 Pages: 775-783
  • DOI: 10.1097/jto.0000000000000170
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells. (2014)
  • Author(s): Tanimoto A, Yano S, et al.
  • Journal Title: Oncotarget Volume: 5 Pages: 4920-8
  • NAID: 120005830567
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Expression of Akt kinase-interacting protein 1, a scaffold protein of the PI3K/PDK1/Akt pathway, in pancreatic cancer. (2014)
  • Author(s): Ohtsubo K, Yano S, et al.
  • Journal Title: Pancreas Volume: 43 Pages: 1093-100
  • DOI: 10.1097/mpa.0000000000000168
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Distinct allelic expression patterns of imprinted IGF2 in adenocarcinoma and squamous cell carcinoma of the lung. (2014)
  • Author(s): Ozaki S, Yano S, et al.
  • Journal Title: Oncol Lett Volume: 8 Pages: 2561-4
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The current state of molecularly targeted drugs targeting HGF/Met. (2014)
  • Author(s): Yano S, Nakagawa T.
  • Journal Title: Jpn J Clin Oncol Volume: 44 Pages: 9-12
  • DOI: 10.1093/jjco/hyt188
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers (2014)
  • Author(s): Ebi H, Yano S, et al.
  • Journal Title: Ｃａｎｃｅｒ Ｓｃｉｅｎｃｅ Volume: 105 Pages: 499505-499505
  • DOI: 10.1111/cas.12383
  • NAID: 120005830600
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: Sensitivity and resistance. (2014)
  • Author(s): Okamoto T, Miyazaki Y, Ogura T, Chida K, Kohno N, Kohno S, Taniguchi H, Akagawa S, Mochizuki Y, Yamauchi K, Takahashi H, Johkoh T, Homma S, Kishi K, Ikushima S, Konno S, Mishima M, Ohta K, Nishioka Y, Yoshimura N, Munakata M, Watanabe K, Miyashita Y, Inase N.
  • Journal Title: Respir Investig Volume: 51 Pages: 191-199
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages (2014)
  • Author(s): Mitsuhashi A, Yano S, et al.
  • Journal Title: The American Journal of Pathology Volume: 182 Pages: 1843-1853
  • DOI: 10.1016/j.ajpath.2013.01.030
  • Peer Reviewed
• [Journal Article] Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma. (2014)
  • Author(s): Moriya M, Yano S, et al.
  • Journal Title: Oncol Rep Volume: 31 Pages: 1109-15
  • DOI: 10.3892/or.2013.2948
  • Peer Reviewed
• [Journal Article] Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. (2013)
  • Author(s): Nanjo S, Yano S, et al.
  • Journal Title: PLoS ONE Volume: 8
  • DOI: 10.1371/journal.pone.0084700
  • NAID: 120005368227
  • Peer Reviewed
• [Journal Article] Paracrine activation of MET promotes peritoneal carcinomatosis in scirrhous gastric cancer (2013)
  • Author(s): Zhao L, Yano S, et al.
  • Journal Title: Cancer Science Volume: 104 Pages: 1640-1646
  • DOI: 10.1111/cas.12301
  • NAID: 120005830610
  • Peer Reviewed
• [Journal Article] EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition (2013)
  • Author(s): Nakagawa T, Yano S, et al.
  • Journal Title: Cancer Res Volume: 73 Pages: 2428-2434
  • DOI: 10.1158/0008-5472.can-12-3479
  • Peer Reviewed
• [Journal Article] Novel PI3K-mTOR inhibitor, BEZ235, circumvents erlotinib -resistance of EGFR mutant lung cancer cells triggering by HGF. (2013)
  • Author(s): Sano T, Yano S, et al.
  • Journal Title: IntJ Cancer Volume: 133 Pages: 505-13
  • DOI: 10.1002/ijc.28034
  • Peer Reviewed
• [Journal Article] mTOR Inhibitors Control the Growth of EGFR Mutant Lung Cancer Even after Acquiring Resistance by HGF. (2013)
  • Author(s): Ishikawa D, Yano S, et al.
  • Journal Title: Plos One Volume: 8
  • DOI: 10.1371/journal.pone.0062104
  • Peer Reviewed
• [Journal Article] Akt kinase-interacting protein 1,a novel therapeutic target for lung cancer with EGFR activating and gatekeeper mutations. (2013)
  • Author(s): Yamada T, Yano S, et al.
  • Journal Title: Oncogene Volume: 32 Pages: 4427-35
  • DOI: 10.1038/onc.2012.446
  • NAID: 120004997024
  • Peer Reviewed
• [Journal Article] Synchronous triple cancers of the pancreas, stomach, and cecum treated with S-1 followed by pancrelipase treatment of pancreatic exocrine insufficiency. (2013)
  • Author(s): Ohtsubo K, Yano S, et al.
  • Journal Title: JOP Volume: 14 Pages: 515-20
  • Peer Reviewed
• [Journal Article] KDM5B histone demethylase controls epithelial-mesenchymal transition of cancer cells by regulating the expression of the microRNA-200 family. (2013)
  • Author(s): Enkhbaatar Z, Yano S, et al.
  • Journal Title: Cell Cycle Volume: 12 Pages: 2100-12
  • DOI: 10.4161/cc.25142
  • Peer Reviewed
• [Journal Article] PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. (2013)
  • Author(s): Ebi H, Yano S, et al.
  • Journal Title: PNAS Volume: 110 Pages: 21124-9
  • DOI: 10.1073/pnas.1314124110
  • Peer Reviewed
• [Journal Article] Endoscopic Findings of Upper Gastrointestinal Lesions in Patients with Pancreatic Cancer (2012)
  • Author(s): Ohtsubo K, Yano S, et al.
  • Journal Title: JOP Volume: 13(4) Pages: 420-6
  • DOI: 10.6092/1590-8577/749
  • Peer Reviewed
• [Journal Article] Hsp90 Inhibition Overcomes HGF-Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis (2012)
  • Author(s): Koizumi H, Yamada T, Takeuchi S, Nakagawa T, Kita K, Nakamura T, Matsumoto K, Suda K, Mitsudomi T, and Yano S
  • Journal Title: J Thoracic Oncol Volume: Vol. 7: no.7 Pages: 1078-1085
  • DOI: 10.1097/jto.0b013e3182519a2c
  • NAID: 40019570662
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer. (2012)
  • Author(s): Yamada T, Takeuchi S, Kita K, Bando H, Nakamura T, Matsumoto K, Yano S
  • Journal Title: J Thoracic Oncol Volume: 7 Pages: 272-280
  • DOI: 10.1097/jto.0b013e3182398e69
  • Peer Reviewed
• [Journal Article] Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI. (2012)
  • Author(s): Uramoto H, Yano S, et al.
  • Journal Title: Anticancer Res Volume: 32(9) Pages: 3785-90
  • Peer Reviewed
• [Journal Article] Therapeutic antitumor efficacy of anti-epidermal growth factor receptor antibody, cetuximab, against malignant pleural mesothelioma. (2012)
  • Author(s): Kurai J, Chikumi HT, Hamada H, Yano S, , Hashimoto K, Takata M, Sako T, Yamaguchi K, Kinoshita N, Watanabe M, Touge H, Makino H, Igishi Shimizu E
  • Journal Title: Int J Oncol Volume: 41 Pages: 1610-1618
  • DOI: 10.3892/ijo.2012.1607
  • Peer Reviewed
• [Journal Article] T790M is associated with a favorable prognosis in Japanese patients treated with an EGFR-TKI. (2012)
  • Author(s): Uramoto T, Yano S, Tanaka F
  • Journal Title: Lung Cancer Volume: 76 Pages: 129-130
  • DOI: 10.1016/j.lungcan.2012.01.010
  • Peer Reviewed
• [Presentation] Therapeutic activity of glycoengineered anti-GM2 antibody BIW-8962 against malignant pleural mesothelioma. (2015)
  • Author(s): Yano S.
  • Organizer: 15th Annual Targeted Therapies of The Treatment of Lung Cancer
  • Place of Presentation: Hotel Fairmont Miramar Wilshire Boulevard (USA)
  • Year and Date: 2015-02-19
• [Presentation] Bone microenvironment conferes Hsp90 inhibitor resistance in the metastatic small sell lung cancer. (2015)
  • Author(s): Yano S.
  • Organizer: Joint International Symposium on TGF-βFamily and Cancer
  • Place of Presentation: International Congress Center EPOCHAL TSUKUBA (Japan)
  • Year and Date: 2015-01-12
• [Presentation] Resistance to EGFR-TKI in EGFR mutant lung cancer. (2014)
  • Author(s): 矢野聖二
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25
• [Presentation] 脳転移：腫瘍内科の視点から. (2014)
  • Author(s): 矢野聖二
  • Organizer: 第52回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-08-28
• [Presentation] 肺がんの骨転移のメカニズムと分子標的治療. (2014)
  • Author(s): 矢野聖二
  • Organizer: 第23回日本がん転移学会学術集会・総会
  • Place of Presentation: 金沢市文化ホール
  • Year and Date: 2014-07-10
• [Presentation] 肺がんの分子標的治療薬耐性の機構解明と耐性克服治療開発. (2014)
  • Author(s): 矢野聖二
  • Organizer: 第18回日本がん分子標的治療学会学術集会
  • Place of Presentation: ホテルメトロポリタン仙台
  • Year and Date: 2014-06-25
• [Presentation] 日本における腫瘍内科教育の今後～分子標的薬体制の克服絵を目指した研究を通して～ (2014)
  • Author(s): 矢野聖二
  • Organizer: 第111回日本内科学会講演会
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2014-04-11
• [Presentation] Strategy to Treat EGFR-TKI Resistance in EGFR Mutant Lung Cancer. (2012)
  • Author(s): Yano S.
  • Organizer: 5th Asia Pacific Lung Cancer Conference.(APLCC)
  • Place of Presentation: Hilton Fukuoka Sea Hawk
  • Year and Date: 2012-11-26
• [Presentation] Ligand-stimulated receptor activation as novel targets to overcome resistance to molecular targeted drugs in lung cancer. (2012)
  • Author(s): 矢野聖二
  • Organizer: 第71回日本癌学会学術集会
  • Place of Presentation: ロイトン札幌
  • Year and Date: 2012-09-19
• [Presentation] Molecular mechanisms of EGFR- TKI resistance and strategy with HGF-Met inhibitors to overcome the resistance. (2012)
  • Author(s): 矢野聖二
  • Organizer: 第10回日本臨床腫瘍学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2012-07-26
• [Presentation] Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor-resistance in EML4-ALK lung cancer cells. (2012)
  • Author(s): Yano S.
  • Organizer: AACR Molecularly Targeted Therapies: Mechanisms of Resistance Conference
  • Place of Presentation: The Westin San Diego
  • Year and Date: 2012-05-09
• [Presentation] 分子標的薬剤の耐性機序及びその耐性克服を目指した臨床戦略.
  • Author(s): 矢野聖二
  • Organizer: 第22回日本がん転移学会学術集会・総会
  • Place of Presentation: ホテル ブエナビスタ
• [Presentation] Mechanisms of EGFR-TKI resistance and therapeutic strategies.
  • Author(s): 矢野聖二
  • Organizer: 第11回日本臨床腫瘍学会学術集会
  • Place of Presentation: 仙台国際センター
• [Presentation] Circumvention of molecular targeted drug-resistance in lung cancer.
  • Author(s): 矢野聖二
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Mechanisms of EGFR-TKI resistance and therapeutic strategies in lung cancer.
  • Author(s): 矢野聖二
  • Organizer: 第54回日本肺癌学会総会
  • Place of Presentation: ホテルニューオータニ
• [Presentation] Novel acquired resistance of molecular-targeted therapy for lung cancer.
  • Author(s): Yano S.
  • Organizer: American Thoracic Society 2013. (Meet the Professor)
  • Place of Presentation: Pennsylvania Convention Center, USA
• [Presentation] Resistance to EGFR TKIs.
  • Author(s): Yano S.
  • Organizer: IASLC 15th World Conference on Lung Cancer
  • Place of Presentation: Sydney Exhibition & Convention Centre, Australia
• [Remarks] 金沢大学附属病院がん高度先進治療センター 金沢大学がん進展制御研究所/腫瘍内科
  • URL: http://syuyounaika.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学附属病院 がん高度先進治療センター 金沢大学がん進展制御研究所／腫瘍内科
  • URL: http://syuyounaika.w3.kanazawa-u.ac.jp/
• [Remarks]
  • URL: http://syuyounaika.w3.kanazawa-u.ac.jp
• [Patent(Industrial Property Rights)] 肺癌患者の治療の有効性の予測検査方法及び肺癌治療剤のスクリーニング方法 (2013)
  • Inventor(s): 矢野聖二、竹内伸司、中川学之
  • Industrial Property Rights Holder: 矢野聖二、竹内伸司、中川学之
  • Filing Date: 2013-03-04